CN113813234B - Effervescent tablet containing stiripentol solid dispersion and preparation method thereof - Google Patents

Effervescent tablet containing stiripentol solid dispersion and preparation method thereof Download PDF

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CN113813234B
CN113813234B CN202111055361.2A CN202111055361A CN113813234B CN 113813234 B CN113813234 B CN 113813234B CN 202111055361 A CN202111055361 A CN 202111055361A CN 113813234 B CN113813234 B CN 113813234B
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stiripentol
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何伟
王影
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China Pharmaceutical University
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Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an effervescent tablet containing stiripentol solid dispersion and a preparation method thereof. According to the effervescent tablet, on one hand, insoluble drugs are prepared into amorphous solid dispersion, so that the water solubility and the dissolution rate of the effervescent tablet are improved, the defect that the gastrointestinal permeability is reduced by other solubilizing means is overcome, and the effervescent tablet has a high encapsulation rate (16.67-50%); on the other hand, the commonly available and safe enteric material is selected as a solid dispersion carrier to ensure that the stiripentol is released in a positioning way in the small intestine and cannot be dissociated in advance in physiological solution like other preparation means, so that the medicine is damaged by gastric acid; in addition, compared with the existing marketed preparation (capsule and dry suspension), the effervescent tablet overcomes the problem that the content is easy to agglomerate, and has the advantages of stable storage, convenient taking, good taste, particular suitability for epileptic children who cannot swallow solid preparations and the like.

Description

Effervescent tablet containing stiripentol solid dispersion and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an effervescent tablet containing stiripentol solid dispersion and a preparation method thereof.
Background
Stiripentol (STP) belongs to BCS II drugs with low water solubility and high permeability, and slow and incomplete dissolution in the gastrointestinal tract is the rate-limiting step of oral absorption. Common methods for increasing apparent solubility of drugs include generation of soluble salts, modification of crystal form/formation of solvates, co-crystallization, solubilization with surfactants, use of cosolvents/cosolvents, formation of inclusion compounds or nanoscale delivery systems, etc., but these methods increase drug solubility and simultaneously decrease drug permeability, thereby affecting oral drug absorption. Because drug permeability is related to the membrane/water partition coefficient, which in turn is determined by drug solubility, there is a unique correlation between drug solubility and permeability. Unlike the former rule of intrinsic relationship between solubility and permeability, the amorphous solid dispersion increases the solubility of the drug by maintaining its supersaturation state, which has no influence on the membrane/water distribution coefficient of the drug, but rather increases the intestinal permeability of the drug, thereby increasing its bioavailability in vivo.
Because the stiripentol is easily degraded by gastric acid, the bioavailability in vivo is extremely low, and the oral absorption fraction is only 0.21%. Thus, the commercial formulations typically require high doses (up to 4g per day) and must be taken at meals (to be protected from gastric acid), resulting in strong side effects and poor patient compliance. A few reports on improving the gastric acid degradation resistance of STP include that STP is protected from being damaged by gastric acid in a passive wrapping or slow-release mode through micelles, nano-emulsions, protein-stabilized drug nano-suspensions and the like, and the synthesis steps of materials used in the systems are complicated 1 The safety of the material is not good enough 2 Reduced drug permeability 3 Low drug loading 4 Or easily dissociated in physiological solution 3 Or aggregate 4 And the like. The invention selects the commonly available and highly biocompatible enteric material, prepares STP into solid dispersion, and improves the intestinal permeability of the medicament while increasing the medicament solubility; but also ensures the positioning release of the drug and endows the drug with the property of resisting gastric acid degradation; in addition, the system has better stability and higher drug loading.
Disclosure of Invention
One of the objects of the present invention is to prepare a solid dispersion of stiripentol. The indissolvable drug is prepared into solid dispersion, the drug is converted into amorphous or microcrystalline state from crystalline state, the drug dissolution does not need to overcome lattice energy, the dissolution is enhanced, and the intestinal permeability is improved; the carrier of the solid dispersion is enteric-coated material, which can endow the drug with gastric acid degradation resistance.
The invention also aims to provide a prescription composition of the stiripentol effervescent tablet and a preparation method thereof. The prescription composition and the preparation method are simple and easy to control, and the prepared effervescent tablet can be stably stored, is convenient to take, has good taste and is more convenient for clinical use.
A stiripentol effervescent tablet is characterized in that: dispersing stiripentol in enteric-coated carrier to obtain solid dispersion, mixing with effervescent disintegrant and filler, and making into effervescent tablet.
The stiripentol solid dispersion is characterized in that:
1) The mass ratio of the drug to the carrier in the solid dispersion is 1-1 (w/w), preferably 1.
2) The drug loading of the solid dispersion is 16.67-50%.
3) The solid dispersion carrier is made of enteric material selected from one or more of Eudragit L100, eudragit S100, HPMCAS, CAP, HPMCP, PVAP, CAT and shellac, preferably Eudragit L100.
The preparation method of the solid dispersion comprises the following steps:
1) Accurately weighing the stiripentol and the enteric material in a certain mass ratio, sequentially dissolving the stiripentol and the enteric material in a proper amount of mixed solvent, performing water bath ultrasonic treatment until the stiripentol and the enteric material are completely dissolved, and performing vortex oscillation to fully mix the stiripentol and the enteric material;
2) Placing the clear and transparent mixed solution on a rotary evaporator, selecting proper temperature and rotation speed, and carrying out rotary evaporation for a certain time under vacuum to remove the organic solvent;
3) After the resulting dried solid system was stored in a desiccator at room temperature for 24 hours, it was taken out and pulverized into coarse particles, and it was sieved to obtain a solid dispersion.
The preparation method of the solid dispersion is characterized by comprising the following steps:
1) The mixed solvent used in the step 1) is ethanol and dichloromethane, and the volume ratio of the ethanol to the dichloromethane is 1.
2) The temperature of rotary evaporation in the step 2) is 40-65 ℃, and preferably 40-45 ℃; the rotating speed of the rotary evaporator is 100-200 rpm, preferably 180-200 rpm; the rotary evaporation time is 45 to 180 minutes, preferably 60 to 90 minutes.
3) The mesh number of the screen for sieving the coarse particles of the solid dispersion in the step 3) is 60-200 meshes, and preferably 80-100 meshes.
The effervescent tablet is characterized in that: the dosage of each component is as follows according to the total weight of the tablet:
Figure BDA0003254403580000021
preferably, the dosage of each component is as follows based on the total weight of the tablet:
Figure BDA0003254403580000022
the preparation of the effervescent tablet is characterized in that:
1) The acid source of the effervescent disintegrant is selected from one of citric acid, malic acid, boric acid, tartaric acid, fumaric acid and hydrochloric acid, the alkali source of the effervescent disintegrant is selected from one of sodium bicarbonate, sodium carbonate and a mixture of sodium bicarbonate and sodium carbonate, and preferably, citric acid and sodium bicarbonate are respectively used as the acid source and the alkali source.
2) The filler in the effervescent tablet adjuvants is selected from one of direct compression type mannitol, lactose monohydrate, and pregelatinized starch, preferably direct compression type mannitol.
3) The preparation method of the effervescent tablet is selected from one of wet granulation, dry granulation and direct powder compression, and the dry granulation compression method is preferred.
The preparation method of the effervescent tablet comprises the following steps:
1) Pretreatment of
Drying the raw and auxiliary materials in a 60 ℃ oven for 1h, then sieving with a 80-150 mesh sieve, preferably a 80 mesh sieve, and placing in a silica gel drier for later use.
2) Powder mixing and granulation
Precisely weighing the effervescent disintegrant acid component and the filler according to the prescription amount, and fully mixing to obtain a mixture 1; accurately weighing the effervescent disintegrant alkali component and the stiripentol solid dispersion in the prescription amount, and fully mixing to obtain a mixture 2; and finally, uniformly mixing the mixture 1 and the mixture 2, immediately pressing into a flaky object with proper hardness, crushing the flaky object into coarse particles, and sieving the coarse particles through a 20-mesh sieve for finishing the particles for later use.
3) Tabletting
Precisely weighing the granules obtained in the step 2) in the prescription amount, and tabletting by using a tabletting machine to obtain the effervescent tablet with smooth and complete surface, proper hardness and disintegration time limit meeting the pharmacopoeia requirements.
Specifically, the method comprises the following steps:
the invention provides the following technical scheme:
1) Preparation of stiripentol enteric solid dispersion
100mg of setripentol and 500mg of Eudragit L100 were precisely weighed, and dissolved in 4mL of a mixed solvent (ethanol: dichloromethane =1,v/v) in turn, both were dissolved completely by water bath sonication, and then vortexed for 2 minutes. The organic solvent was removed on a rotary evaporator at 45 ℃ under vacuum at 180 rpm. The resulting dried solid system was stored in a desiccator at room temperature for 24 hours before pulverization and sieving, and then, after taking out and pulverizing into coarse particles, it was sieved through a 80-mesh sieve to obtain a solid dispersion.
2) Preparation of stiripentol effervescent tablet
The prescription of the effervescent tablet comprises the following components:
Figure BDA0003254403580000031
the preparation method comprises the following steps:
drying the raw and auxiliary materials in a 60 ℃ oven for 1h, then sieving with a 80-150 mesh sieve, preferably with a 80 mesh sieve, and placing in a silica gel dryer for later use. Precisely weighing the effervescent disintegrant acid component and the filler according to the prescription amount, and fully mixing to obtain a mixture 1; accurately weighing the effervescent disintegrant alkali component and the stiripentol solid dispersion in the prescription amount, and fully mixing to obtain a mixture 2; and finally, uniformly mixing the mixture 1 and the mixture 2, immediately pressing into tablets with proper hardness, crushing the tablets into coarse particles, sieving the coarse particles by a 20-mesh sieve for finishing the particles, immediately tabletting by using a tabletting machine to obtain the effervescent tablets with smooth and complete surfaces, proper hardness and disintegration time limit meeting the pharmacopoeia requirements.
Dissolution of a poorly soluble and highly permeable drug, i.e., a Biopharmaceutical Classification System (BCS) class II drug, is the rate-limiting step in oral absorption. There are several methods currently used to improve the dissolution of such drugs, such as drug nanocrystals, solid dispersions, cyclodextrin inclusion compounds, liposomes, microemulsions, nanoparticles, or micelles. Solid dispersions are widely used by pharmaceutical workers due to their advantages of easy preparation, good solubilization effect, etc. Solid Dispersion (SD) refers to a dispersion system in Solid form formed by uniformly dispersing a drug in a carrier in a highly dispersed state such as a molecular, amorphous, microcrystalline state, etc. As an intermediate of a pharmaceutical preparation, the solid dispersion can increase the dissolution rate of insoluble drugs, improve the bioavailability, delay the release of the drugs and simultaneously increase the stability of the drugs.
Dry granulation is a process in which the drug is mixed with diluents, disintegrants, lubricants and other excipients, then pressed into a sheet of desired hardness by rolling or pressing, and then pulverized into granules. Products that are temperature and humidity sensitive (e.g. effervescent disintegrant ingredients) are particularly suitable for dry granulation. Compared with wet granulation, dry granulation has the advantages of time saving, energy saving, simple process, capability of avoiding contact with water to increase the stability of effervescent tablets and the like.
The key steps in the invention comprise: screening a prescription in the preparation process of the solid dispersion (determining the screening mesh number and the mass ratio of the medicament to the carrier), determining the effervescent tablet prepared by a dry granulation method, and determining the type of the filling agent in the effervescent tablet and the proportion of the using amount of each component.
The best prescription of the effervescent tablet is as follows (according to the weight of the tablet being 100 mg):
Figure BDA0003254403580000041
has the advantages that:
1. compared with the STP preparation (capsule and dry suspension) on the market, the effervescent tablet prepared by STP has the following advantages: the effervescent disintegrant has good mouthfeel like soda water, and is easier to be accepted by patients; the preparation is prepared into suspension in drinking water before use, is convenient to take and is particularly suitable for epileptic children who cannot swallow solid preparations; the effect is quick, the bioavailability is high, and the clinical curative effect can be improved; can be stored stably, and has no problems of easy caking of contents and the like.
The invention firstly disperses the indissolvable drug in the enteric soluble carrier to prepare solid dispersion, so that the drug is converted into amorphous or microcrystalline state from the crystalline state, the solubility is improved, the intestinal permeability is also improved, and the enteric material is protected to prevent the drug from being degraded by gastric acid, so that the bioavailability is improved; then, the solid dispersion and proper auxiliary materials are mixed and pressed into effervescent tablets, and the effervescent tablets are prepared into a preparation form which can be stably stored, is convenient to take and has good taste, and are particularly suitable for epileptic children who cannot swallow the solid preparation.
2. The invention prepares the indissolvable drug into the solid dispersion, so that the drug is changed into an amorphous state from a crystal state, the dissolution of the drug does not need to overcome lattice energy, and the dissolution is easier and faster; the carrier of the solid dispersion is enteric material, which endows the drug with the characteristic of resisting gastric acid degradation and is beneficial to improving the bioavailability in vivo.
3. The invention provides a prescription of a stiripentol effervescent tablet and a preparation method thereof. The formula composition is simple, the effervescent tablet is simple in preparation process, and the stability of the effervescent tablet can be improved by avoiding contact with water, so that the prepared effervescent tablet can be stably stored, is convenient to take, has good taste and is more convenient for clinical use.
Drawings
FIG. 1 is a schematic diagram of the preparation process of stiripentol solid dispersion and effervescent tablet in the present invention;
FIG. 2 is a graph showing the effect of different mesh sizes on the dissolution behavior of solid dispersions in gastric and intestinal fluids; wherein A is the cumulative dissolution amount of the solid dispersion in gastric fluid within 2 hours, and B is the time taken for the solid dispersion to dissolve 90% in intestinal fluid;
FIG. 3 is a graph showing the effect of different mass ratios of drug carrier ratios on drug content, saturation solubility and dissolution behavior in solid dispersions; wherein A is the saturated solubility of the solid dispersions with different mass ratios, B is the drug content of the solid dispersions with different mass ratios, C is the accumulated dissolution amount of the solid dispersions with different mass ratios in gastric juice within 2 hours, and D is the time taken for the solid dispersions with different mass ratios to dissolve 90 percent in intestinal juice;
FIG. 4 is SEM electron microscope result picture of bulk drug and solid dispersion;
FIG. 5 is a graph of solid state characterization (A-C are PXRD, DSC, FTIR, respectively) results for drug, carrier, physical mixture of drug and carrier, and solid dispersion;
FIG. 6 is a graph showing the results of content stability of the solid dispersion at room temperature and 4 ℃ for three months;
FIG. 7 is a graph comparing dissolution behavior of effervescent tablets with that of the original ground and solid dispersion on the market;
FIG. 8 is a graph comparing the apparent permeability coefficient of solid dispersions to that of bulk drugs.
Detailed Description
The starting materials or reagents used in the present invention are commercially available.
And (3) determining the content, saturation solubility and dissolution behavior of the medicine on the solid dispersion or effervescent tablet:
1) Determination of drug content
The solid dispersion or effervescent tablets (to be ground) corresponding to 10mg STP were weighed accurately, dissolved in 10mL of methanol and dissolved by sonication. After filtration through a 0.45 μm filter and appropriate dilution, the absorbance at 301nm was measured with an ultraviolet spectrophotometer. Using the formula Drug Content (%) = (M) sample 100) x 100%, calculating the drug content.
2) Saturated solubility determination
The solubility was determined under supersaturated conditions (C >10 Cs). To 10mL of distilled water, simulated gastric fluid and simulated intestinal fluid was added an excess of STP (i.e., a solid dispersion equivalent to 20mg of STP). The sample was placed in a shaking water bath shaker, stirred at 50rpm for 48h (appropriate equilibration time), and then placed at 37 ℃ for 12h. After completion, all samples were centrifuged at 4000rpm for 10min. The supernatant was filtered through a Millipore membrane filter (pore size 0.45 μm), and after appropriate dilution the STP content was determined using an ultraviolet spectrophotometer at 301 nm.
3) Dissolution determination
The solid dispersions were tested for dissolution on a ZRS-4 intelligent dissolution tester using the paddle method in the pharmacopoeia. A solid dispersion corresponding to 10mg STP was weighed out and fresh degassed 500mL artificial gastrointestinal fluid containing 1% (w/v) Tween 80 (SGF composition: HCl (84 mmol/L) and NaCl (34 mmol/L); SIF composition: KH) was placed in 2 PO 4 (50 mmol/L) and NaOH (23.6 mmol/L)), which was maintained at 37. + -. 0.5 ℃ by means of a circulating water bath and stirred at 100 rpm. The amount of elution was 2h in SGF, and when specifiedAt time points (10, 20, 30, 45, 60, 90, 120 min) 6mL aliquots were taken and replaced with an equal volume of fresh simulated gastric fluid. The amount eluted was examined for 3.5h in SIF and 6mL aliquots were taken at specific time points (10, 20, 30, 45, 60, 90, 120, 180, 210 min) and replaced with an equal volume of fresh simulated intestinal fluid. Immediately filtered through a 0.45 μm filter and diluted appropriately, and quantified spectrophotometrically at 301 nm. The percentage STP of cumulative dissolution was plotted as a function of time.
The formation of the solid dispersion was verified by techniques such as Scanning Electron Microscopy (SEM), powder X-ray diffraction (PXRD), differential Scanning Calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR).
The invention is further illustrated with reference to the accompanying drawings and specific examples.
STP: stiripentol
Eu L100：Eudragit L100
SD: solid dispersion
PM: physical mixture of stiripentol and Eudragit L100
SGF: simulated gastric juice
SIF: simulated intestinal fluid
Example 1: prescription optimization and solid state characterization of solid dispersions
The preparation flow is shown in fig. 1, and the prescription optimization and solid-state characterization are as follows:
1) Effect of mesh number on dissolution behavior of solid Dispersion in gastric and intestinal fluids
100mg of stiripentol and 400mg of Eudragit L100 were precisely weighed, dissolved in 3mL of a mixed solvent (ethanol: dichloromethane =1,v/v) in sequence, and both were completely dissolved by water bath sonication, followed by vortex shaking for 2 minutes. The organic solvent was removed on a rotary evaporator at 45 ℃ under vacuum at 180 rpm. The resulting dried solid system was stored in a desiccator at room temperature for 24 hours before crushing and sieving, after which the crushed coarse particles were taken out and sieved through 60, 80 and 100 mesh sieves, respectively, to obtain solid dispersions of different sizes for dissolution testing.
The results are shown in fig. 2, the smaller the SD particles (i.e. the higher the mesh number of the screen) are, the higher the cumulative dissolution amount in 2h in gastric fluid is, which is attributable to the fact that the smaller the particle size is, the larger the contact surface with the dissolution medium is, the higher the dissolution amount is; and the smaller the particle size, the shorter the time required for 90% or more to be dissolved in intestinal juice. Considering that STP is used in epilepsy patients, it is required that the drug acts rapidly to reduce the possibility of injury or death of the patient, and due to its characteristic of being easily destroyed by gastric juice, it is expected that SD will dissolve less in gastric juice and rapidly in intestinal juice, so an 80-mesh screen is the best choice.
2) Effect of drug carrier ratios of different mass ratios on drug content, saturation solubility and dissolution behavior in solid dispersions
Stiripentol and Eudragit L100 (1, 2, 1, 3, 1, 4, 1. The organic solvent was removed on a rotary evaporator at 45 ℃ under vacuum at 180 rpm. Storing the obtained dried solid system in a dryer for 24 hours at room temperature before crushing and sieving, taking out the solid system crushed into coarse particles, sieving the coarse particles with a 80-mesh sieve to obtain solid dispersions with different mass ratios, and respectively measuring the drug content, the saturated solubility and the dissolution of the solid dispersions.
As shown in FIG. 3, the drug contents of the solid dispersions with different mass ratios were all between 95% and 105%; and the higher the carrier content, the higher the saturated solubility of SD in various media; the higher the carrier content, the less the cumulative SD dissolves in gastric juice and the faster the SD dissolves in intestinal juice. In conclusion, the optimal mass ratio is selected from the group consisting of the drug loading ratio of 1.
3) Morphological characterization of solid dispersions
The surface morphology of STP and its solid dispersions was examined using a scanning electron microscope (Hitachi S-4800). The dried samples were dipped in conductive gel and sputter coated with gold prior to microscopic examination. The micrographs were taken at an excitation voltage of 20 kV. The magnifications chosen were 100 x and 200 x, sufficient to observe the general morphology of the powders studied.
As shown in FIG. 4, the STP crystal was found to be irregular fine particles with a smooth surface and a size of about 40 μm by SEM observation, and was partially agglomerated. Since the solid dispersion is prepared by a solvent evaporation method, it has a sheet-like structure with a size of about 200 μm. From the SD scanning map, the solid dispersion is relatively uniform in both surface and side cross section, and no obvious heterogeneous particles are observed, which indicates that STP is uniformly dispersed in the enteric polymer carrier and is prevented from being damaged by gastric acid in the oral administration process.
4) Characterization of the crystalline state of solid dispersions
The X-ray patterns of the samples were characterized using a Bruker D8 Advance X-ray diffractometer. The test samples were packed into 0.5mm deep graphite sample holders. The sample was scanned at a scanning speed of 1 deg./min in the range of 3-50 deg. 2-theta with a step length of 0.02 deg. and a step time of 1s. The pattern was collected with monochromatic CuK α radiation (λ =0.154 nm) at 40kV and 60 mA.
The results are shown in fig. 5, with pure STP showing sharp crystalline diffraction at 6.245 ° and other minor peaks at 11.994 °, 15.909 °, 17.643 °, 18.870 °, 19.122 °, 25.227 °, and 31.697 ° in the 2 θ range. Eudragit L100 shows a weak fluctuation between 10 and 20 degrees 2 theta but has no crystalline peak due to its amorphous nature. In the PM, both the weak fluctuation of the carrier and the characteristic diffraction peak generated by the drug are shown, indicating that the drug in the PM is still in a crystalline state. In SD, the characteristic peak of the drug disappears, indicating that the drug in SD is dispersed in the carrier in an amorphous state, and it is likely that there is an interaction between the drug and the carrier, resulting in a decrease in the crystallinity of the drug.
5) Thermodynamic state characterization of solid dispersions
Powdered STP, eudragit L100, the physical mixture and SD (3-5 mg) were sealed in an aluminium pan and heated at a constant rate of 10 ℃/min in the temperature range of 30-300 ℃. Their thermograms were obtained using a NETZSCH DSC model 204 differential thermal analyzer. Thermoanalytical data were recorded using a TA 50 ipc system with Shimadzu software program. The indium standard solution was used to calibrate the DSC temperature and enthalpy scale. N is a radical of 2 A rate of 50mL/min was used as the purge gas.
The results are shown in figure 5 where STP begins to absorb heat at 75.1 ℃ and forms a sharp endothermic peak, probably due to melting of STP, which is approximately 75 ℃. The endothermic peak in Eudragit L100 represents its glass transition process, since the temperature at which the onset of the endotherm is very close to the theoretical Tg (. About.195 ℃) of Eudragit L100. The corresponding physical mixture shows an endothermic curve corresponding to the melting point of STP indicating that crystallinity is still present in the PM, i.e. that a portion of the STP is still in crystalline form. No STP melting peak was observed in the SD thermogram, indicating that STP is in an amorphous state in the solid dispersion.
6) Validation of drug-carrier interaction in solid dispersions
Powdered STP, eudragit L100, physical mixture and SD were mixed with potassium bromide (KBr) and compressed into disks, respectively. The scan range is 4000-450cm-1, the resolution is 1.0cm-1, and the average number of scans per sample is 20. The infrared spectrum was measured using a Bruker tesser model 27 infrared spectrometer.
The result is shown in FIG. 5, and the characteristic region (4000-1250 cm) in the PM infrared spectrum -1 ) And a fingerprint area (1250-400 cm) -1 ) Both are simple overlays of the STP and Eudragit L100 maps, with no interaction between the two. V in SD compared to pure STP crystals O-H (3600～3200cm -1 ) And V C＝O (～1728cm -1 ) The region shows a broader absorption bandwidth, probably due to hydrogen bonding between the secondary hydroxyl groups of STP and the carboxyl or carbonyl groups of the support polymer. In addition, hydrogen bonding association often results in V C-H (3000～2850cm -1 ) The STP is submerged, only the peak top is exposed, and the two can be verified again that the STP is uniformly dispersed in the carrier through hydrogen bond interaction, and the STP is kept in an amorphous state for a long time, so that the STP is not easy to convert to a crystalline state in the storage process.
7) Standing stability study of solid Dispersion
The required amounts of STP, eudragit L100, PM, SD were placed in aluminum foil self-sealing bags and evaluated for content stability at room temperature and refrigerated (4 ℃) for 3 months.
As a result, as shown in FIG. 6, the solid dispersion could be maintained at room temperature and in a refrigerated (4 ℃) environment for at least 3 months without content change.
Example 2: preparation method and prescription screening of effervescent tablets
1) Optimization of effervescent tablet preparation method
For the powder direct compression method, all auxiliary materials are respectively sieved by a 80-mesh sieve, then anhydrous citric acid with the prescription amount is mixed with direct compression mannitol for 10 minutes to obtain a mixture 1, sodium bicarbonate with the prescription amount is mixed with a solid dispersion for 10 minutes to obtain a mixture 2, and finally the mixture 1 and the mixture 2 are fully mixed and immediately compressed. In the case of dry granulation tableting, the flakes obtained by the powder direct compression method are crushed into coarse particles, and then the particles are sized by a 20-mesh sieve, and tableting is performed immediately according to the amount prescribed. For wet granulation and tabletting, all auxiliary materials are respectively sieved by a 80-mesh sieve, then anhydrous citric acid with the prescription amount is mixed with direct compression mannitol for 10 minutes, 10 microliters of purified water is used as a binding agent to prepare a soft material, the soft material is sieved by a 20-mesh sieve to prepare wet granules, the wet granules are placed in an oven at 60 ℃ for drying for 1 hour, the granules are sieved by the 20-mesh sieve to obtain a mixture 1, then sodium bicarbonate with the prescription amount is mixed with a solid dispersion for 10 minutes to obtain a mixture 2, and finally, the mixture 1 and the mixture 2 are fully mixed and immediately tableted.
Table 1 shows the results of the screening of the effervescent tablet preparation method:
Figure BDA0003254403580000081
the results are shown in table 1, the effervescent tablets prepared by the three methods are complete and smooth in appearance, and the weight difference, hardness and disintegration time of the tablets are within the limits required by pharmacopoeia. By comprehensively considering all measured indexes, the tablet obtained by dry granulation has higher hardness and quickest disintegration, and ensures that moisture-sensitive ingredients (such as effervescent disintegrant) can not contact with water, and finally dry granulation tabletting is determined.
2) Optimization of filler type and each component dosage in effervescent tablet preparation
The formulations in table 2 below were compressed into effervescent tablets using a dry granulation process and tablet properties were evaluated:
table 2 recipe exploration for dry granulation:
Figure BDA0003254403580000091
table 3 is a graph of the results of screening the dosage of each component and the type of the bulking agent of the effervescent tablet:
Figure BDA0003254403580000092
as a result, as shown in Table 3, the kind of filler does not greatly affect the hardness and disintegration time of the tablet, while the ratio of the amounts of the respective components greatly affects the tablet properties. SD (30%), citric acid anhydrous (20%), sodium bicarbonate (20%), mannitol (30%) were finally chosen as the optimal prescription, as this set of tablets is moderately hard and disintegrates faster.
3) Dissolution behavior of the optimal effervescent tablet compared to the original ground state and solid dispersion
And precisely weighing the solid dispersion, the original grinding agent and the effervescent tablet which are equivalent to 10mg STP, and performing dissolution investigation in the artificial gastrointestinal fluid. The amount of elution was examined in SGF for 2h and in SIF for 3.5h and the percentage STP of cumulative elution was plotted as a function of time.
The results are shown in fig. 7, where the effervescent tablets substantially agreed with the dissolution behavior of the solid dispersion; compared with the original preparation, the effervescent tablet and the solid dispersion dissolve less in gastric juice, dissolve more quickly in intestinal juice and have more total dissolution amount. This shows that the preparation of stiripentol into enteric solid dispersion can not only enhance the dissolution of the drug, but also reduce the loss of the drug in gastric juice, and is expected to improve the bioavailability.
Example 3: research on penetration enhancement effect of stiripentol solid dispersion in intestinal perfusion experiment
1) Physiological saline: 9g of NaCl was precisely weighed and dissolved in 1000mL of water.
2) Chloral hydrate injection: 3.3g of chloral hydrate was precisely weighed, and the volume was adjusted to 100mL with physiological saline.
3) Krebs-Ringer buffer: every 10 th00mL of water contained 7.8g of NaCl,0.35g of KCl,0.37g of CaCl 2 ,0.22gMgCl 2 ,0.22g NaH 2 PO4,1.4g C 6 H 12 O 6 ,1.37g NaHCO 3 The buffer pH was adjusted to 7.4 with phosphoric acid or sodium hydroxide.
4) Intestinal perfusion fluid: accurately weighing an appropriate amount of STP solid dispersion, and preparing the STP solid dispersion into a buffer solution with the pH of 7.4 Krebs-Ringer to the concentration of 100 mu g/mL -1 The intestinal perfusion solution is dissolved by ultrasonic for standby use and is used as a test solution. 20mg of STP raw material medicine is precisely weighed, and 200mL of STP suspension solution is prepared by Krebs-Ringer buffer solution with pH7.4 and is used as a control.
5) In vivo intestinal perfusion experiment of rat
Rats were fasted for 12h before the experiment, during which time water was freely available. Chloral hydrate (3.3%, 1mL/100 g) was injected intraperitoneally, and after anesthesia, a small incision was cut along the ventral midline, exposing a section of the rat intestine. The duodenum segment starts 3cm below the pylorus, the jejunum 20cm below the pylorus, and the ileum 15cm before the ileocecal valve. Each section of intestine is about 10cm long, and the two ends are inserted with tubes and tightened. Discharging the content of the intestinal segment with 37 deg.C normal saline, changing into blank Krebs-Ringer buffer solution, balancing at flow rate of 1mL/min for 10min, then changing into 37 deg.C perfusion solution containing medicine, rapidly filling the intestinal segment, reducing flow rate to 0.2mL/min, and collecting the perfusion solution at the outlet of each intestinal segment within 2h. After the experiment, the rat is sacrificed, and the perfused intestine section is taken out, cleaned, cut off and provided with coordinate paper, and the length and the inner diameter are measured. Collecting perfusate sample, adding appropriate amount of methanol to dissolve the medicine, centrifuging at 15000rpm for 10min, collecting supernatant 10 μ L, injecting into high performance liquid chromatograph, and measuring initial mass concentration C of solid dispersion 0 And the total mass concentration C in each intestinal segment within 2h 2h . The apparent permeability coefficient was calculated according to the following formula: initial amount of stiripentol in intestinal perfusion: x 0 ＝C 0 ×V 0
Residual amount of stiripentol in intestinal perfusion fluid: x t ＝C t ×V t
Calculating the apparent permeability coefficient of the medicament by adopting a mass conservation method:
Figure BDA0003254403580000101
wherein Q is perfusion rate (mL)Min); l and r are the length (cm) and cross-sectional radius (cm) of the perfused intestinal segment, respectively.
The result is shown in fig. 8, compared with the bulk drug, the solid dispersion of stiripentol can enhance the apparent permeability coefficient of the solid dispersion in duodenum, jejunum and ileum, thereby being beneficial to improving the in vivo bioavailability of the solid dispersion.
Reference to the literature
1.Zhang,X.；Wang,H.；Zhang,T.；Zhou,X.；Wu,B.,Exploring the potential of self-assembled mixed micelles in enhancing the stability and oral bioavailability of an acid-labile drug.European Journal ofPharmaceutical Sciences 2014,62,301-308.
2.Dai,Q.；Zhang,P.；Jin,Y.；Tang,M.；Shen,M.；Xu,S.；Huang,S.；Chen,Y.,Using Self-Nanoemulsifying System to Improve Oral Bioavailability of a Pediatric Antiepileptic Agent Stiripentol:Formulation and Pharmacokinetics Studies.AAPS PharmSciTech 2020,21(5),192.
3.Lu,R.；Liu,S.；Wang,Q.；Li,X.,Nanoemulsions as novel oral carriers ofstiripentol:insights into the protective effect and absorption enhancement.Int J Nanomedicine 2015,10,4937-4946.
4.He,W.；Wang,Y.；Lv,Y.；Xiao,Q.；Ye,L.；Cai,B.；Qin,C.；Han,X.；Cai,T.；Yin,L.,Denatured protein stabilized drug nanoparticles:tunable drug state and penetration across the intestinal barrier.Journal of Materials Chemistry B 2017,5(5),1081-1097.

Claims (4)

1. A solid dispersion characterized by: the drug is dispersed in a carrier material to prepare the drug-carrier composite, and the mass ratio of the drug to the carrier is 1;
the drug is stiripentol;
the carrier of the solid dispersion is Eudragit L100;
the solid dispersion is prepared by the following steps:
1) Weighing the raw materials according to the mass ratio of the medicine to the carrier of the solid dispersion, sequentially dissolving the raw materials in a mixed solvent, and performing water bath ultrasonic treatment until all the raw materials are completely dissolved; the used mixed solvent is ethanol and dichloromethane, and the volume ratio of the ethanol to the dichloromethane is 1 to 2;
2) Putting the solution obtained in the step (1) into rotary evaporation to remove the organic solvent; wherein the rotary evaporation temperature is 40 to 65 ℃; the rotating speed of the rotary evaporator is 100 to 200 revolutions per minute; the rotary steaming time is 45 to 180 minutes;
3) Drying and storing the obtained dry solid system at room temperature for 24 hours, taking out and crushing the system into coarse particles, and sieving the coarse particles to obtain a solid dispersion; wherein the coarse particles of the solid dispersion are sieved by a sieve with 60 to 200 meshes.
2. An effervescent tablet comprising the stiripentol solid dispersion of claim 1, characterized in that: the dosage of each component is calculated by weight of a single piece (100 mg):
30 to 60 mg of stiripentol solid dispersion
The acid component of the effervescent disintegrant is 10 to 30 mg
The alkali component of the effervescent disintegrant is 10-30 mg
10 to 40 mg of a filler
The acid component of the effervescent disintegrant is one of citric acid, malic acid, boric acid, tartaric acid, fumaric acid and hydrochloric acid; the alkali component of the effervescent disintegrant is one of sodium bicarbonate, sodium carbonate and their mixture;
the filler is any one of direct compression type mannitol, lactose monohydrate and pregelatinized starch.
3. An effervescent tablet according to claim 2, wherein: the preparation method of the effervescent tablet comprises any one of wet granulation, dry granulation and direct powder tabletting.
4. A process for the preparation of effervescent tablets as claimed in claim 3, which comprises the following steps:
1) Pretreatment of
Drying the raw and auxiliary materials in an oven at 60 ℃ for 1h, and then sieving the dried raw and auxiliary materials in a silica gel drier with a sieve of 80 to 150 meshes for later use;
2) Powder mixing and granulation
Precisely weighing the effervescent disintegrant acid component and the filler according to the prescription amount, and fully mixing to obtain a mixture 1; accurately weighing the effervescent disintegrant alkali component and the stiripentol solid dispersion in the prescription amount, and fully mixing to obtain a mixture 2; finally, uniformly mixing the mixture 1 and the mixture 2, immediately pressing into a sheet with proper hardness, crushing the sheet into coarse particles, and sieving the coarse particles through a 20-mesh sieve for finishing the particles for later use;
3) Tablet press
Precisely weighing the granules obtained in the step 2) in the prescription amount, and tabletting by using a tabletting machine to obtain the effervescent tablets.
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